The human IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ra, IL-2Rb, and gc. Dr. Leonard cloned IL-2Ra in 1984, his group discovered IL-2Rb in 1986, and reported in 1993 that mutation of the gc chain results in X-linked severe combined immunodeficiency (XSCID, which has a T-B+NK- phenotype) in humans. This group reported in 1995 that mutations of the gc-associated kinase, Jak3, result in an autosomal recessive form of SCID indistinguishable from XSCID and in 1998 that T-B+NK+ SCID results from mutations in the IL7R gene. Based on work in this lab and others, gc was previously shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The group also previously characterized genes that were induced or repressed by IL-2, IL-4, IL-7, and IL-15, including showing the negative regulation of the IL-7 receptor alpha chain, a finding with implications in understanding how IL-2 can promote cell death, and the positive regulation of a dual specificity phosphatase, DUSP5, that negatively regulates IL-2-mediated activation of ERK kinases. The group has also extended its work on mechanisms of signaling by these cytokines. In prior work, the group also had identified and studied thymic stromal lymphopoeitin (TSLP), whose binding protein, TSPLR is most related to gc, and showed that although both TSLP and IL-7 share the IL-7 receptor alpha chain, the function of TSLP and IL-7 are distinctive, that mouse TSLP plays a distinctive role in CD4 T cell development whereas IL-7 and IL-15, which also share gc, favor CD8 T cell developmen, and that TSLP plays a critical role in the develop of asthma in a mouse model system. In the current year, the lab has extended studies related to genes regulated by gc dependent cytokines and further analyzed the actions of TSLP.[unreadable] [unreadable] In addition, having previously published the cloning of the IL-21 receptor and had created IL-21 transgenic mice and IL-21R knockout mice and shown that IL-21 critically regulates immunoglobluin production in mice as well as inducing B cell apoptosis, in the past year, the group reported that IL-21 is a major inducer of terminal differentiation into plasma cells, with the ability to stimulate both peripheral memory B cells and even cord blood human T cells. Having previously provided data suggesting that IL-21 may contribute to the pathogenesis of a murine model of systemic lupus erythematosis, the group has extended its investigation in this area in work intended to more definitively establish a relationship of IL-21 to autoimmune disease in general and SLE in particular. Having demonstrated previously that IL-21 potently cooperates with either IL-7 or IL-15 to augment the expansion of CD8+ T cells and that this potently augmente anti-tumor effects in a murine model of melanoma, the group has substantiated extended these studies.[unreadable] [unreadable] Overall, these studies help to improve our understanding of signaling by IL-2 and related cytokines. These findings clarify the molecular mechanisms for immunodeficiency and are relevant to autoimmunity and cancer, as well as to the basic control of T-cell and B-cell actions.